23+26 Flashcards
How do we obtain specificity in biology?
Specificity in molecular interactions relies on:
Molecular shape: different molecules fitting together like a 3D jigsaw
Chemical complementarity: positive charges interacting with negative charges, hydrogen bonding potential fulfilled, clusters of hydrophobic moieties
Spatiotemporal overlap: molecules being in the same place at the same time
So where does the API come from?
Natural Products
Source of the earliest drugs
- Semi-synthetic
Derivatives of natural products
Receptor selectivity - Synthetic
Small molecule drugs
Large biological drugs
Sources of Natural Products
Natural products may be extracted from cells, tissues and secretions.
These may come from -Microorganisms
Penicillin
-Plants Tannins Alkaloids Paclitaxel Morphine -Animals Conotoxins
natural product- morphine
Derived from the seedpods of the poppy,Papaver somniferum(opium) has been used for thousands of years by early civilizations
By the 1800’s in Europe, opium was the painkiller of choice for physicians, but its effects were hard to predict.
Friedrich Sertürner (1783-1841)sought to isolate the active ingredient in opium, from which predictable and reliable doses could then be produced.
Friedrich named his new drug for the Greek god of dreams, Morpheus, but to keep it consistent with standard naming conventions, labeled it morphine.
In addition to being sold as an analgesic, initially morphine was also marketed as a non-addictive cure for addiction to both alcohol and opium.
Semi-Synthetic Drugs
sem·i·syn·thet·ic (sem’ē-sin-thet’ik),
Describing the process of synthesizing a particular chemical using a naturally occurring chemical as a starting material, thus obviating part of a total synthesis, for example, the conversion of cholesterol (obtained from a natural source) into a corticosteroid.
Advantages: Reliability of production, cost effective, quality control
Disadvantages: Limited chemical space, limited number of steps, IDENTITY OF TARGET?
What are the advantages of semi-synthesis?
Components of the molecule are ‘complex’ and too difficult to synthesise chemically.
Limited availability from natural sources
Modification of a natural compound can result in altered receptor selectivity or improved specificity, leading to additional/alternative uses.
Semi-Synthetic Drugs
- taxol
In the early 1960’s, Jonathan Hartwell of the US National Cancer Institute organized collection of plants from the U.S. for evaluation as potential sources of anticancer drugs.
One plant collected as part of the NCI program was the Pacific yew, Taxus brevifolia, and the extract was confirmed as active in an animal test system. Component identified as Taxol.
Taxol interferes with cell division by binding to the protein tubulin, which is a key factor in mitosis. Unlike some other cancer drugs which prevented tubulin from assembling into microtubules, taxol bound to assembled microtubules and blocked them from disassembling.
At their peak, Pacific yew bark collections were several hundred thousand pounds of bark per year.
The bark from a single tree only yielded enough taxol for about one dose of the drug.
Semi-Synthetic Drugs- Morphine analogues
Modification of a natural compound can result in alternative receptors selectivity or improved specificity, leading to additional/alternative uses.
Modification of morphine results in opioid analogues with varying potency and receptor specificity.
There are three types of opioid receptors.
Chemical modifications to morphine can change which receptor type (m, k, d) the compound binds to and the effect it causes (agonist, antagonist).
Drug Design
In the case of natural products (and many semi-synthetic drugs), Nature has evolved and produced the API for us.
In drug design, we need to rationally discover the identity of the API using a series of techniques and methods. This is referred to as Rational Drug Design.
Druggable Targets
When designing a drug, there are a number of targets we can focus on:
Enzymes
Receptors
Ion channels
Substrates, Metabolites and Proteins
Transport systems
DNA/RNA and the ribosome
Physicochemical mechanism
There are a number of key factors which make a target ‘druggable’.
Target is disease-modifying and/or has a proven function in the pathophysiology of a disease.
Modulation of the target is less important under physiological conditions or in other diseases.
Target expression is not uniformly distributed throughout the body.
Properties of an ideal drug target:
If the druggability is not obvious (e.g. as for kinases) a 3D-structure for the target protein or a close homolog should be available for a druggability assessment.
Target has a favorable ‘assayability’ enabling high throughput screening.
A target/disease-specific biomarker exists to monitor therapeutic efficacy.
Favorable prediction of potential side effects according to phenotype data (e.g. in k.o. mice or genetic mutation databases).
Target has a favorable IP situation (no competitors on target, freedom to operate).
Drug Molecules
Lipinski’s Rule of Five does a good job of quantifying drug like properties. According to this rule a drug should have:
molecular weight < 500
a log P < 5
< 5 hydrogen bond donors
< 10 hydrogen bond acceptors
Drug Molecules- shape
A drug molecule possesses one or more functional groups positioned in three-dimensional space on a structural framework that holds the functional groups in a defined position that enables the molecule to bind specifically to a targeted biological macromolecule, the receptor.
